Feline immunodeficiency virus (FIV) is a lentivirus which causes immunodeficiency syndrome in domestic cats (Pedersen et al., 1987; Siebelink et al., 1990). FIV closely resembles human immunodeficiency virus (HIV) in genomic, biochemical, and morphologic characteristics as well as clinical and hematological manifestations (Johnson et al., 1994; Pedersen et al., 1987; Yamamoto, Sparger et al., 1988). As a result, FIV infection of domestic cats is considered to be an excellent small animal model for testing prophylactic and therapeutic strategies against AIDS viruses (Gardner, 1991; Johnson et al., 1994). A number of antiretroviral drugs for HIV, including the prototype nucleoside analogue azidothymidine (AZT), has been tested using the FIV model (Hart et al., 1995; Hartmaun et al., 1992; Hayees et al., 1993; Hayees et al., 1995; Meers et al., 1993; North et al., 1989; Smith et al., 1994).
The therapeutic use of AZT has been unremarkable in cats and was unable to delay the spread of FIV infection in vivo (Hart et al., 1995; Hartmaun et al., 1992).
Prophylactic AZT treatment of experimental cats caused either a delay or decrease in both infected blood lymphocyte numbers and plasma virus load (Hayees et al, 1993; Hayees et al., 1995; Meers et al., 1993; Smith et al., 1994). In addition, a delay in FIV antibody production was observed in some animals (Smith et al., 1994). However, prophylactic therapy with AZT did not protect cats from FIV infection (Meers et al., 1993; Hayees et al., 1993; Hayees et al., 1995; Smith et al., 1994). As reported for HIV therapy, withdrawal of the drug resulted in a resurgence of the virus in these cats. When compared to the untreated group, significantly higher CD4 and CD8 cell counts were observed shortly after the withdrawal of the drug (Hayees et al., 1993; Hayees et al., 1995). However, CD4/CD8 ratios were not significantly different from the untreated cats. In contrast, FIV-infected cats therapeutically treated with AZT had no change in FIV antigen or anti-FIV antibody titers but had transient improvement in CD4/CD8 ratios and clinical signs (Hart et al., 1995; Hartmaun et al., 1992). These findings suggest that monotherapy with AZT has limited benefit as a therapy for FIV infection. Similar observations have been made with AZT monotherapy of HIV-infected individuals (Harrigan, 1995; Staszewski, 1995).
In recent trials, combination therapies with AZT and other antiretroviral drugs, such as phosphonomethoxyethyl) adenine and dideoxycytidine 5′-triphosphate, had minimal to no effect in preventing or controlling FIV infection in cats (Hartmaun et al., 1992; Magnani et al., 1994; Philpott et al., 1992). The in vivo use of viral protease inhibitors or new nucleoside analogue combinations, such as, for example, lamivudine (3TC) and AZT has yet to be reported in FIV-infected cats. Commercially available HIV protease inhibitors (e.g., Sequinavir (SQV), Indinavir (IDV), Ritonavir, Nelfinavir) do not inhibit FIV replication in PBMC in vitro. Unlike other nucleoside analogues, 3TC rapidly induces mutations which can phenotypically reverse the mutations caused by AZT, enabling the antiviral activity of AZT to persist in the host (Boucher et al., 1993; Larder, 1995; Tisdale et al, 1993). This unique feature of 3TC makes it a prime candidate for use in combination with AZT. In HIV-positive individuals, the combination AZT/3TC therapy had synergistic or additive effects at decreasing plasma virus load and increasing CD4 cell counts and function (Katlama et al., 1994; Lange, 1995; Paul et al., 1995; Staszewski, 1995). The addition of an HIV protease inhibitor to this combination further decreased the viral load and improved the CD4 cell count (Deeks et al., 1997; Torres et al., 1997).